Computational Studies On The Influence Of Side-chain Interactions Of Trp-cage Mini-protein On Its Structural Folding Dynamics Based On Statistical Analysis Of PDB Coil Library

Protein structure corresponding to natively-folded state is the biophysical basis for its biological function.Protein inter-residue interactions,its folding mechanism and the relationship between them have always been focused in structural biology.Molecular dynamics(MD)simulation can describe the atomic details of protein folding,and its effectiveness depends on the accuracy of force field.Two independent MD simulation with two different force fields(OPLSAA/L and optimized OPLSAA/C force field based on PDB coil library)were used to conduct on the Trp-cage folding mechanism in this paper.The results show that the Trp-cage mini-protein eventually collapse into a mis-folded(M)state(RMSD = 6.8 ?,Q = 0.1)within 0.5 or 1.0-?s MD simulation under the OPLSAA/L force field,and its mis-folding pathway can be decomposed into four steps: D (?) Ts (?) I (?) M.However,the Trp-cage structure can quickly fold into a nearly native conformation(N,RMSD = 1.2 ?,Q = 0.95)within 1.0-?s MD run under the OPLSAA/C force field,and its folding pathway was: D (?) I1 (?) I2 (?) N,in accordance with the diffusion-collision mechanism.These results indicate that the folding accuracy and conformation sampling efficiency can be effectively improved by using the OPLSAA/C force field based on statistical analysis of intrinsic conformational features of PDB coil library.The OPLSAA/C force field was then adopted to further investigate the influence of sidechain properties on its structural folding.The results indicate that the N1 G,S13G,R16 G,P18G,and S20 G mutation can fold into a nearly native state.Their secondary and tertiary structures are well formed with only slight damage to their local structure of the mutated site;However,the secondary and tertiary structures are severely destroyed in the I4 G,W6G,L7 G,K8G and P19 G mutations.The other seven mutations including L2 G,Y3G,Q5 G,D9G,P12 G,S14G,and P17 G are partially unfolded and misfolded without perfect secondary unit and completely hydrophobic pocket.The results demonstrate that the synergistic interaction between residues is crucial for its structural folding.The residues with the same sidechain(Ser13 and Ser14)exhibit the opposite orientation,their contributions to its structural stability and folding dynamics differs significantly from each other.Finally,computational calculations and biological experiments were combined to explore the binding affinities of protein AlepPBP1 from A.lepigone and two sex pheromones(Z7-12: Ac and Z9-14: Ac).The hydrophobic interactions involved by several non-polar residues inside the AlepPBP1 are identified to be the main driving force for its binding to Z7-12: Ac(Phe36,Trp37,Phe118)and Z9-14: Ac(Phe36,Trp37,Val52,Phe118).It is consistent with the driving force of the Trp-cage formation.These findings provide theoretical guidance for protein structural optimization and active-site modification.